Erythropoietin is known for its activity in stimulating erythroid progenitor cell survival, proliferation and differentiation. Erythropoietin is produced in the interstitial cells of the kidney in a hypoxic responsive manner and is used in treatment of anemia in patients with chronic kidney disease. High dose erythropoietin treatment in mice resulted in reduced blood glucose level in addition to increased hematocrit, suggesting that erythropoietin may affect metabolic homeostasis. Erythropoietin treatment decreased fasting blood glucose level in both normal diet fed mice and high fat diet fed mice, compared with mice treated with saline. Since hematopoietic tissue is the major target of erythropoietin, we speculate that erythropoietin may stimulate glucose uptake in hematopoietic tissue, especially during erythroipoiesis. We examined cultures of human erythroid progenitor cells isolated from peripheral blood and found that glucose uptake per cell increased with erythroid differentiation and peaked in late erythroid progenitor cells, then decreased during terminal differentiation. Glucose uptake appeared to follow erythropoietin receptor expression and was maximal when erythropoietin receptor levels were highest; glucose uptake decreased as erythropoietin receptor levels decreased with the progression of erythroid maturation to mature erythrocytes that no longer express erythropoietin receptor. No induction of gamma-globin gene expression was observed. The combination of erythropoietin with elevated glucose resulted in a transient increase in gamma-globin gene expression and increased hemoglobinization. While this activity of elevated glucose level in combination with EPO affects the erythroid differentiation program, change in the resultant gamma/(gamma + beta) globin ratio is minimal by the end of the culture period. These data suggest that high dose glucose during erythropoietin stimulated erythroid differentiation results in premature hemoglobin accumulation and differentiation with no great change in proportion of fetal hemoglobin production.